The present invention relates to novel fourth and/or sixth position substituted 5-hydroxy2,3-dihydrobenzothiophenes useful as inhibitors of leukotriene biosynthesis.
Copending U.S. patent application Ser. No. 230,825 (CN 17729) of Caldwell et al filed Aug. 12, 1988, discloses and claims fourth and/or sixth position substituted 5-hydroxy-2,3 dihydrobenzofurans useful as inhibitors of leukotriene biosynthesis.
During the progression of inflammatory conditions, there is generally an appearance and/or presence of macrophages and lymphocytes, especially polymorphonuclear leukocytes. These cells are known to secrete various products in response to inflammatory stimuli. The arachidonic acid oxygenation products, in particular, have been identified as the critical mediators of various inflammatory conditions. Inhibition of arachidonic acid oxidation by enzyme inhibition has been explored as effective therapy. For example, non-steroidal anti-inflammatory drugs (NSAID) such as aspirin, indomethacin and diflunisal are known cyclooxygenase inhibitors which inhibit the process wherein arachidonic acid is oxygenated via cyclooxygenase to prostaglandins and thromboxanes.
Recently, it has been observed that certain leukotrienes are responsible for diseases related to immediate hypersensitivity reactions such as human asthma, allergic disorders, and skin diseases. In addition, certain leukotrienes and derivatives thereof are believed to play an important role in causing inflammation (B. Samuelsson, Science, 220, 568 (1983); D. Baily et al, Ann. Rpts. Med. Chem., 17, 203 (1982)).
Accordingly, pharmacological agents which are capable of inhibiting the formation or the release of a mediator and thereby interfere with the function of macrophages or polymorphonuclear leukocytes may also be effective agents in the treatment of various inflammatory conditions, e.g., pain, fever, rheumatoid arthritis, osteoarthritis, bronchial inflammation, inflammatory bowel disease, asthma, allergic disorders, skin diseases, cardiovascular disorder, glaucoma, emphysema, acute respiratory distress syndrome, spondylitis, lupus, gout and psoriasis.
The human polymorphonuclear leukocytes assay, has been found to be a useful indicator of the ability of compounds to inhibit leukotriene biosynthesis. Known inhibitors of leukotriene biosynthesis, agents such as phenidone and nordihydroguaiaretic acid, for example, are active in this assay (C. J. Blackwell and R. J. Flower, Prostaglandins, 16, 417 (1978); J. Chang, M.D. Skowronek, M. L. Cherney and A. J. Lewis, Inflammation, 8, 143 (1984)).